The inventors disclose a novel type of ligand-cytotoxic drug conjugates in WO2016/127790. The ligand-cytotoxic drug conjugates and the pharmaceutical compositions comprising the same have good effects in the preparation of a medicament for treating cancer by receptor regulation. In the synthesis of such ligand-cytotoxic drug conjugates, the compound of formula (I) of the present invention is an important intermediate.

This intermediate has a similar structure to Mc-MMAF disclosed for the first time in the patent application WO2005/038392 by Seattle Genetics (U.S.A.), which discloses the synthetic of Mc-MMAF. However, in the synthetic route, there is no detailed disclosure of a specific preparation process for Fmoc-Dolaproine (Fmoc-Dap) and the starting materials. Fmoc-Dolaproine (Fmoc-Dap) has a similar chemical structure to the key intermediate of formula (IV), which is used synthesizing the compound of formula (I) of the present invention.

Therefore, the inventors identified related synthetic routes in the prior art of synthesizing Fmoc-Dolaproine (Fmoc-Dap). For example, George R. Pettit and Matthew P. Grealish reported a synthesis method of adding methyl directly in J. Org. Chem. 2001, 66, 8640-8642 (see Scheme 1), and a method of adding methyl after hydrolysis in Synthesis. 1996. 720 (see Scheme 2).


When synthesizing the fused ring substrate of formula (IV) of the present invention, the inventors used the above synthetic method of synthesizing Fmoc-Dolaproine (Fmoc-Dap), which a relatively high yield in the premise of original substrate. However, when the fused ring substrate of formula (IV) of the present invention was prepared, the yield of the target product was low and a amount of racemate was produced. Therefore, there are still a lot of difficulties and shortcomings in using the existing synthetic methods to synthesize the compound of formula (I) in a large scale. It is necessary to develop a method with a high yield that is suitable for the large-scale synthesis of the compound of formula (I).